Orally administered drugs are typically formulated into tablets or capsules. For most drugs, to maintain the drug level in the body above the minimal therapeutically effective level, these dosage forms are administered frequently (every 4 hr, 6 hr, 8 hr etc). Such administration schedule can lead to patience non-compliance and therapeutic complication due to repeated incidence of missed doses, especially when the patient is administering multiple drugs. To address this issue, drugs are formulated into extended release dosage forms, where multiple doses are combined into the dosage form to be released over an extended period of time, thereby reducing the dosing frequency to once or twice daily.
While there are several approaches to extend the drug release from orally administered dosage forms, they can be generally classified to reservoir or matrix systems [Colombo et al., 2008, Swellable and Rigid Matrices: Controlled Release Matrices with Cellulose Ethers. In: Pharmaceutical Dosage Forms: Tablets, Volume 2: Rational Design and Formulation. Third Edition, Augsburger, L. and Hoag, S. (eds.). Informa Healthcare, New York, London]. Reservoir systems are based on coating a drug loaded core with water insoluble polymers or lipids through which drug diffusion is slow. Matrix systems are based on using either plastic or gelling materials to form tortuous or highly viscous matrices respectively. The increased tortuosity or viscosity leads to slower drug diffusion and hence slower release from the dosage form. For both systems, the amount of release-extending excipient used is dictated by several factors, most notably the drug solubility, dose and the intended release rate. For highly water-soluble drugs, a high level of release-extending excipient is required in addition to other excipients, such as binders and lubricants, needed to form robust tablets. The requirement for a high excipient load makes formulating high dose drugs particularly challenging since it is difficult to maintain the final dosage form size within a suitable range for swallowing, e.g. 1 gram or less.
Another challenge for formulating an extended release dosage form for drugs with high dose and high aqueous solubility is the susceptibility of the release-extending elements to alcohol induced dose-dumping which can be fatal. For example, in 2005, the FDA requested the manufacturer of once-daily hydromorphone extended release capsules to suspend its product sales citing serious and potentially fatal adverse reactions that occurred when the product was taken together with alcohol. Several of the pharmaceutical grade excipients used to control drug release are soluble in alcohol rendering the corresponding dosage form susceptible to alcohol induced dose-dumping. These excipients include, but are not limited to, ethyl cellulose, polyethylene glycol, poly(oxyethylene, oxypropylene), poly(methacrylic acid, methyl methacrylate), poly(methacrylic acid, ethyl acrylate), poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride), poly(butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate), cetosteryl alcohol, polyvinyl acetate phthalate and shellac.
Due to the alcohol susceptibility of many of the pharmaceutical grade excipients, formulators have resorted to using lipid matrices to extend the drug release and impart alcohol resistance owing to the insolubility of most lipids in alcohol or hydroalcoholic solvents. However, using lipids matrices to extend drug release carries several disadvantages including:                1. Physical and chemical instability of the lipids. Most lipids are prone to rancidity on storage via a complex free radical reaction (Craig, D. Q. M., 2004. Lipid Matrices for Sustained Release-An Academic Review. Bulletin Technique Gattefosse No 97).        2. Nearly all lipids are also prone to physical state transformation (polymorphic transition, crystallization and/or amorphization) which can affect the dosage forms characteristics and performance (Souto, E. B., Menhert, W., Muller, R. H., 2006. Polymorphic behavior of Compritol®888 ATO as bulk lipid and as SLN and NLC. J. Microencaps. 23(4), 417-433. Hamadani, J., Moes, A. J., Amighi, K., 2003. Physical and thermal characterization of Precirol® and Compritol® as lipophilic glycerides used for the preparation of controlled release matrix pellets. Int. J. Pharm., 260, 47-57).        3. Lipid based extended release dosage forms are prone to in vitro dissolution profiles changes on aging (Khan, N and Craig, D. Q. M., 2004. The role of blooming in determining the storage stability of lipid based dosage forms. J. Pharm. Sci., 93, 2962-2971. Choy, Y. W., Nurzaline Khan, Yuen, K. H., 2005. Significance of lipid matrix aging on in vitro release and in vivo bioavailability. Int. J. Pharm., 299, 55-64. San Vicente, A., Hernandez, R. M., Gascon, A. R., Calvo, M. B., Pedraz, J. L., 2000. Effect of aging on the release of salbutamol sulfate from lipid matrices. Int. J. Pharm, 208, 13-21).        4. Simple dosage form manufacturing processes such as tablet and capsule filling are not easily applicable to many lipid systems (Craig, D. Q. M., 2004. Lipid Matrices for Sustained Release-An Academic Review. Bulletin Technique Gattefosse No 97).        5. Extended release dosage forms based on lipidic matrices are more prone to food effect compared to other dosage forms owing to the increased secretion of digestive enzymes with food that affect the integrity of the dosage form.        6. The dependence of the dosage form integrity and hence the release characteristics on the effect of gastrointestinal enzymes caused lipid-based dosage forms to show more inter- and intra-individual variability (Craig, D. Q. M., 2004. Lipid Matrices for Sustained Release-An Academic Review. Bulletin Technique Gattefosse No 97).        
Metoprolol is a selective beta 1-adrenoreceptor blocking agent used to treat hypertension, angina pectoris and myocardial infarction. It is approved in the US in three salt forms, namely the succinate, fumarate and tartrate, where all dosages are calculated in equivalence to the tartrate salt. It is available as immediate release oral tablets (25, 50 and 100 mg equivalent to the tartrate salt), extended release oral tablets or capsules for once daily administration (25, 50, 100, 200, 300 and 400 mg equivalent to the tartrate salt) as well as in ampoules for intravenous injection (1 mg/ml). Both the tartrate and succinate salts are highly soluble in water. The high water solubility and the high dose needed for extended release dosage pose significant challenges to formulating metoprolol salts as alcohol resistant extended release formulations.
The current invention aims to address the above challenges by formulating metoprolol and pharmaceutically acceptable salts (e.g. the tartrate or succinate salt) and solvates (e.g. hydrates) into an alcohol resistant extended release dosage form without resorting to the use of lipids.